The overall goals of this program are to apply new therapeutic and molecular strategies to further improve the treatment of melanoma. Work accomplished during the first two years of this grant established that tamoxifen (TAM) can overcome clinical resistance to cisplatin (DDP) , that there is truly a synergistic interaction between TAM and DDP, and that TAM can delay the development of resistance to DDP. We have also established a new strategy for quantitating the extent of DDP-induced injury to the tumor within 24 hours of treatment. We plan to make use of the interaction between DDP and TAM to further enhance the response rate to the TAM/DDP combination through dose intensification of both agents. The specific aims of this renewal application are to: 1) conduct a phase I trial testing the feasibility of adding TAM in doses of up to 160 mg/day to an already established program in which DDP is administered at a dose of 80 mg/m2 iv every week for 6 doses (nicknamed HICISTAM); 2) conduct a phase II trial of the HICISTAM program in patients with metastatic melanoma; 3) determine whether the magnitude of the induction of DNA damage response genes in melanomas in vivo caused by HICISTAM correlates with clinical response; 4) determine the rate of development of resistance to DDP/TAM of melanomas during treatment with HICISTAM using the magnitude of the DNA damage response gene induction following sequential doses of HICISTAM; and 5) determine the mechanism(s) underlying the synergistic interaction between TAM and DDP. Specifically we will investigate the role of anti-estrogen binding sites (AEBS) in mediating synergy, and its effect on the ability of DDP to trigger an apoptotic response.